PROJECT SUMMARY/ABSTRACT Molecular mechanisms regulating and interpreting BMP signaling Bone morphogenetic proteins (BMPs) belong to the transforming growth factor ? (TGF?) superfamily of ligands and the BMP signaling pathway plays roles in multiple developmental and homeostatic processes. Malfunction of the pathway causes many somatic and hereditary disorders in humans, including cardiovascular diseases and cancer. Thus multiple levels of regulation must exist in vivo to ensure proper spatiotemporal specificity, level, and duration of BMP signaling in the right cellular context. We have developed a novel, highly specific and sensitive genetic screen in C. elegans that has allowed the identification of multiple new and evolutionarily conserved modulators of the BMP pathway. These modulators span from extracellular secreted proteins, to cell surface integral membrane or GPI-anchored proteins, to proteins involved in intracellular trafficking, highlighting many levels of regulation on BMP signaling. Excitingly, several of these factors have not been previously implicated in regulating BMP signaling in any systems. In addition to the regulators, we have also identified a cell type specific target of BMP signaling in the C. elegans postembryonic mesoderm. Determining how the BMP modulators function in regulating BMP signaling and how BMP signaling is interpreted in specific cellular contexts are the research focuses under this MIRA. We propose to use a multifaceted approach that combines molecular genetic, genome editing, biochemical and high- resolution imaging techniques to dissect the functions of the BMP modulators in C. elegans. At the same time, we are also branching out to determine the functions of these factors in mammalian tissue culture cells. Our research has been funded by NIGMS since 2002 when I first set up my lab at Cornell University. Over the years, we have made substantial progress and have generated a set of tools/reagents that put us in a unique position to carry out our proposed research. Our experiences and expertise, coupled with the flexibility offered by the MIRA mechanism to pursue new research opportunities as they arise, will allow us to make sustained progress in our research. Our studies are bound to provide important insights into the complex and intricate mechanisms regulating and interpreting BMP signaling at single cell resolution in a multicellular living animal. They may also provide potential therapeutic targets for the different diseases caused by mutations in the BMP pathway.